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RBM10 Deficiency Promotes Anti-PD-1 Resistance in LUAD via STING Alternative Splicing-Driven CCL7 Signaling and
Weitong Gao1, Ruqiong Wang1, Bo An1
1Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
Abstract:
Although immune checkpoint inhibitors have improved outcomes in lung adenocarcinoma (LUAD), many patients still exhibit inadequate responses. The immunomodulatory functions of RNA-binding motif (RBM) proteins remain poorly understood. Using in vivo and in vitro models of RBM10 deficiency combined with cytokine arrays, CLIP-seq, RIP, and proteomics, we found that RBM10 deficiency promotes an immunosuppressive microenvironment, and targeting key chemokines restored anti-PD-1 efficacy in RBM10-deficient LUAD models. RBM10 deficiency enhanced the polarization and recruitment of M2 tumor-associated macrophages (TAMs), both in vitro and in vivo. Mechanistically, RBM10 loss disrupted STING exon 3 exclusion via alternative splicing and impaired QKI-mediated stabilization of the STING-E3(-) isoform, shifting the splicing balance toward the STING-E3(+) isoform and promoting CCL7 secretion. CCL7 acted through its receptor CCR2 on macrophages, driving M2 polarization and recruitment. This central pathway was further reinforced by a positive feedback loop wherein M2-polarized TAMs transferred mitochondria to tumor cells, potentially contributing to mtDNA-cGAS-STING signaling and sustained CCL7 production. Therapeutically, CCL7/CCR2 blockade synergized with PD-1 inhibition to promote tumor regression in RBM10-deficient tumors. Collectively, RBM10 serves as a key immunoregulator in LUAD by modulating the STING-CCL7-CCR2 axis, and targeting the CCL7-CCR2 axis represents a promising strategy to overcome anti-PD-1 resistance.
Insights
RNA-binding motif 10 (RBM10) deficiency in lung adenocarcinoma (LUAD) creates an immunosuppressive tumor microenvironment. Targeting the CCL7-CCR2 pathway can restore anti-PD-1 therapy efficacy in RBM10-deficient LUAD.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Immune checkpoint inhibitors (ICIs) have improved lung adenocarcinoma (LUAD) treatment outcomes.
- However, many LUAD patients show inadequate responses to ICIs.
- The immunomodulatory roles of RNA-binding motif (RBM) proteins are not well understood.
Purpose of the Study:
- To investigate the role of RBM10 in regulating the tumor immune microenvironment in LUAD.
- To identify mechanisms by which RBM10 deficiency affects anti-tumor immunity and response to ICIs.
- To explore therapeutic strategies to overcome ICI resistance in RBM10-deficient LUAD.
Main Methods:
- In vivo and in vitro models of RBM10 deficiency.
- Cytokine arrays, CLIP-seq, RIP, and proteomics.
- Analysis of macrophage polarization and recruitment.
- Investigated STING splicing and CCL7 secretion.
- Explored the role of the CCL7-CCR2 axis and mitochondrial transfer.
Main Results:
- RBM10 deficiency promotes an immunosuppressive microenvironment in LUAD.
- RBM10 loss impairs STING exon 3 exclusion, leading to increased CCL7 secretion.
- CCL7 recruits and polarizes M2 tumor-associated macrophages (TAMs) via the CCR2 receptor.
- A positive feedback loop involving M2 TAMs and mtDNA-cGAS-STING signaling sustains CCL7 production.
- Targeting chemokines or the CCL7-CCR2 axis restores anti-PD-1 efficacy.
Conclusions:
- RBM10 is a key immunoregulator in LUAD, controlling the STING-CCL7-CCR2 axis.
- RBM10 deficiency drives immunosuppression and resistance to anti-PD-1 therapy.
- Targeting the CCL7-CCR2 axis offers a promising strategy to enhance anti-PD-1 therapy in LUAD.
